Desynchronised times? Chronobiology, (bio)medicalisation and the rhythms of life itself.

This paper takes a critical look at the role of chronobiology in society today, with particular reference to its entanglements with health and medicine and whether or not this amounts to the (bio)medicalisation of our bodily rhythms. What we have here, we show, is a complex unfolding storyline, within and beyond medicine. On the one hand, the promises and problems of these circadian, infradian and ultradian rhythms for our health and well-being are now increasingly emphasised. On the other hand, a variety of new rhythmic interventions and forms of governance are now emerging within and beyond medicine, from chronotherapies and chronopharmacology to biocompatible school and work schedules, and from chronodiets to the optimisation of all we do according to our 'chronotypes'. Conceptualising these developments, we suggest challenges us to think within and beyond medicalisation to wider processes of biomedicalisation and the biopolitics of our body clocks: a vital new strand of chronopolitics today indeed which implicates us all in sickness and in health as the very embodiment of these rhythms of life itself. The paper concludes with a call for further research on these complex unfolding relations between chronobiology, health and society in these desynchronised times of ours.

Substance use, sleep and intervention design: insights from qualitative data.

Background: Alcohol and other drug use is associated with poor sleep quality and quantity, but there is limited qualitative research exploring substance users' experiences of sleep and few psychosocial sleep interventions for them. Aim: To inform the development of psychosocial interventions to improve sleep amongst people reporting drug/alcohol problems. Method: Qualitative data were collected during a sleep survey. Of the 549 drug/alcohol users completing the survey, 188 (34%) provided additional information about their sleep using a free text box. Responses were analysed via Iterative Categorisation. Findings were reviewed with reference to the Behaviour Change Wheel (BCW). Results: All data were categorised inductively under five headings: (i) sleep quality; (ii) nature of sleep problems; (iii) sleep and substances; (iv) factors improving sleep quality; (v) factors undermining sleep quality. Substance use undermined sleep, but poor sleep often persisted after substance use had ceased. Sleep problems were diverse; as were the causes of, and strategies for dealing with, those problems. Causes and strategies had biological, psychological, social and environmental roots. Conclusions: The BCW facilitated the identification of intervention components that might improve the sleep of people who use substances. These components relate to education, training, enablement, modelling, service provision, guidelines and environment.

Disturbing sleep and sleepfulness during recovery from substance dependence in residential rehabilitation settings.

There is evidence that poor sleep mitigates recovery from substance dependence and increases risk of relapse. However, to date research literature is located within biomedical, clinical and psychological paradigms. To complement the extant work, this article offers a sociological exploration of sleep in the context of recovery from dependence on alcohol and/or other drugs. Drawing on qualitative data generated through interviews with 28 men and women living in residential rehabilitation settings in England, we provide a detailed exploration of sleep practices focusing on how these are enacted throughout the night. We offer the concept of 'sleepfulness' to suggest that sleep should not be understood simply as being other than awake; rather it involves a myriad of associations between diverse actants - human and non-human - that come to 'fill up', enable and assemble sleep. Together these empirical insights and conceptualisations disturb the ontology of sleep and point to the fulsome dimensions of the category.

'M-apping' sleep? Trends and transformations in the digital age.

This article critically explores recent trends and transformations in the monitoring and management of sleep in the digital age, taking as its focus the advent of new digital technologies to trace and track the 'sleep of ourselves' far away from the conventional sleep laboratory or clinic. Our argument is situated dually in the history of sleep science and medicine on the one hand, and the rise of new digital forms of so-called self-tracking and mobile health (m-Health) on the other hand. While the recent history of sleep science and medicine may rightly we suggest, in Kroker's terms, be characterised as a concern with the 'sleep of others', a new chapter in this story may well be dawning through the advent of these smart new mobile tools and technologies for mapping, or 'm-apping' as we term it, the 'sleep of ourselves' in the digital age. The problems and prospects this holds are then critically considered - through the interrelated themes of selfhood, sociality and governance - and some preliminary conclusions ventured in this new digital domain.

Partner Alliance to Enhance Efficacy and Adherence of CBT-I.

Cognitive behavioral therapy for insomnia (CBT-I) is now widely recognized as the first-line management strategy for insomnia, both for insomnia in its "pure" form, and when comorbid with a physical or psychological illness. However, there is a definite need to develop and test both alternative and adjunct interventions to CBT-I, before implementing them into routine practice. The aim of this article is to provide a narrative review of the literature with regard to what is known about the influence of partners on sleep, insomnia, and its management.

Are sleep quality judgments comparable across individuals, places, and spaces? An interdisciplinary analysis of data from 207,608 individuals across 68 countries.

OBJECTIVES: Significant research has shown that health is a heterogeneous concept, and one person's poor health may not be comparable with another's. Yet, little consideration has been given to whether sleep quality judgments are also heterogeneous or whether they cohere between individuals. Another possibility is that there are group differences in the ways in which sleep quality is perceived. If this is the case, it is possible known inequalities in sleep are-in part-an artifact of social position influencing how we conceive of sleep problems. The current study explores this possibility. DESIGN: Cross-sectional, using World Health Organization data from 207,608 individuals; aged between 15 and 101 years of age from 68 countries. Alongside a battery of sleep and demographic variables, data contained sleep and energy vignettes. Random effect anchoring vignette models were applied to investigate interpersonal incompatibility and whether sleep quality perceptions operate differently depending on social location, context, and function. RESULTS: While sleep quality judgments are largely comparable across individuals, findings also highlight how the relationship between education and self-reported sleep changes following adjustment for reporting heterogeneity. Estimates of threshold parameters suggest that those with more years of education have a slightly increased threshold for reporting mild sleep problems (B 0.005; s.e. 0.001) but a lower threshold for reporting sleep problems as extreme (B -0.007; s.e. 0.001). CONCLUSIONS: Sleep quality judgments occupy a complex position between heterogeneity and coherence. This has implications for both epidemiological methodologies and contemporary debates about social justice, public health and sleep.

Non-peptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket.

The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide(1) is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3-41microM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.

Conversational agents and the making of mental health recovery.

BACKGROUND: Artificial intelligence (AI) is said to be "transforming mental health". AI-based technologies and technique are now considered to have uses in almost every domain of mental health care: including decision-making, assessment and healthcare management. What remains underexplored is whether/how mental health recovery is situated within these discussions and practices. METHOD: Taking conversational agents as our point of departure, we explore the ways official online materials explain and make sense of chatbots, their imagined functionality and value for (potential) users. We focus on three chatbots for mental health: Woebot, Wysa and Tess. FINDINGS: "Recovery" is largely missing as an overt focus across materials. However, analysis does reveal themes that speak to the struggles over practice, expertise and evidence that the concept of recovery articulates. We discuss these under the headings "troubled clinical responsibility", "extended virtue of (technological) self-care" and "altered ontologies and psychopathologies of time". CONCLUSIONS: Ultimately, we argue that alongside more traditional forms of recovery, chatbots may be shaped by, and shaping, an increasingly individualised form of a "personal recovery imperative".

US Army Combat Medic Performance With Portable Ultrasound to Detect Sonographic Findings of Pneumothorax in a Cadaveric Model.

BACKGROUND: Ultrasound, due to recent advances in portability and versatility, has become a valuable clinical adjunct in austere, resource-limited settings and is well demonstrated to be an accurate/efficient means to detect pneumothorax. The purpose of this study was to evaluate the impact of hands-on ultrasound training on ultrasound-naive US Army combat medics' ability to detect sonographic findings of pneumothorax with portable ultrasound in a cadaver model. METHODS: Ultrasound-naive US Army combat medics assigned to conventional military units were recruited from a single US Army installation and randomized to receive either didactic training only, or "blended" (didactic and hands-on) training on ultrasound detection of pneumothorax. Blinded participants were asked to perform a thoracic ultrasound exam on ventilated human cadaver models. Primary outcome measured was sensitivity and specificity of detecting sonographic findings of pneumothorax between cohorts. RESULTS: Forty-three participants examined a total of 258 hemithoraces. The didactic-only cohort (n = 24) detected sonographic findings of pneumothorax with a sensitivity of 68% and specificity of 57%. The blended cohort (n = 19) detected sonographic findings of pneumothorax with an overall sensitivity of 91% and specificity of 80%. Detection sensitivities were similar between B-mode versus M-mode use. CONCLUSION: US Army combat medics can use portable U/S to detect sonographic findings of pneumothorax in a human cadaver model with high sensitivity after a brief, blended (didactic and hands-on) training intervention.

Gender and socio-economic patterning of self-reported sleep problems in Britain.

Sleep is fundamental to health and well-being, yet relatively little research attention has been paid to sleep quality. This paper addresses how socio-economic circumstances and gender are associated with sleep problems. We examine (i) socio-economic status (SES) patterning of reported sleep problems, (ii) whether SES differences in sleep problems can be explained by socio-demographic characteristics, smoking, worries, health and depression, and (iii) gender differences in sleep problems, addressing the relative contribution of SES, smoking, worries, health and depression in explaining these differences. Logistic regression is used to analyse the British Psychiatric Morbidity Survey 2000, which interviewed 8578 men and women aged 16-74. Strong independent associations are found between sleep problems and four measures of SES: household income, educational qualifications, living in rented housing and not being in paid employment. Income differences in sleep problems were no longer significant when health and other characteristics were adjusted. The higher odds of sleep problems among the unemployed and adults with low education remained significant following adjustment. Women reported significantly more sleep problems than men, as did the divorced and widowed compared with married respondents. Gender differences in sleep problems were halved following adjustment for socio-economic characteristics, suggesting that SES inequalities play a major part in accounting for gender differences in sleep problems. Our study casts doubt on the primacy of physiological explanations underlying these gender differences. Since disadvantaged socio-economic characteristics are strongly associated with sleep problems, we conclude that disrupted sleep may be a mechanism through which low SES is linked to poor health.

Engaging with sleep: male definitions, understandings and attitudes.

Recent literature has highlighted the sociological significance of sleep and has suggested that sleep offers a 'window' onto the gendered nature of our lives. Yet within this body of work men's sleep has been largely ignored. This paper seeks to rectify this omission and situates itself at the intersection between literature on the sociological aspects of sleep and social-constructionist-orientated writings on men's health. It draws upon qualitative data from 40 men to investigate male understandings of, and attitudes towards, sleep. At first glance, it could be suggested that men have little regard for sleep, and are prone to taking risks with their dormancy. Viewed in this way sleep becomes an instrument used in the negotiation of status and power and intrinsically bound up with the demonstration of masculinities. Yet, men's relationship with sleep is more complex than this. Amongst other things, the men within the present study were embroiled in a function/non-function dichotomy. Sleep was seen as needed for the praxis of 'father', 'worker', 'husband' and 'mate' but was also considered as something which should not get in the way of performing these roles.

Development and early validation of a patient-reported outcome measure to assess sleep amongst people experiencing problems with alcohol or other drugs.

Study Objectives: To develop a patient-reported outcome measure to assess sleep amongst people experiencing problems with alcohol or other drugs. Methods: Item development included secondary analyses of qualitative interviews with drug or alcohol users in residential treatment, a review of validated sleep measures, focus groups with drug or alcohol users in residential treatment, and feedback from drug or alcohol users recruited from community and residential settings. An initial version of the measure was completed by 549 current and former drug or alcohol users (442 in person and 107 online). Analyses comprised classical test theory methods, exploratory and confirmatory factor analysis, measurement invariance assessment, and item response theory (IRT). Results: The initial measure (30 items) had good content and face validity and was named the Substance Use Sleep Scale (SUSS) by addiction service users. After seven items were removed due to low item-factor loadings, two factors were retained and labeled: "Mind and Body Sleep Problems" (14 items) and "Substance-Related Sleep Problems" (nine items). Measurement invariance was confirmed with respect to gender, age, and administration format. IRT (information) and classical test theory (internal consistency and stability) indicated measure reliability. Standard parametric and nonparametric techniques supported convergent and discriminant validity. Conclusions: SUSS is an easy-to-complete patient-reported outcome measure of sleep for people with drug or alcohol problems. It can be used by those concerned about their own sleep, and by treatment providers and researchers seeking to better understand, assess, and potentially treat sleep difficulties amongst this population. Further validity testing with larger and more diverse samples is now required.

Sleep waves and recovery from drug and alcohol dependence: Towards a rhythm analysis of sleep in residential treatment.

This paper reports on a study of sleep amongst men and women who are living in residential rehabilitation centres in the UK and who are receiving support for their recovery from addiction to alcohol and other forms of substance use. Conceptually and methodologically, the paper draws on the work of the French sociologist Lefebvre and, in particular, his rhythmanalysis. We argue that this approach offers a useful way of exploring sleep in terms of biological, experiential, temporal, spatial and social rhythms. It also has the potential to facilitate interdisciplinary dialogue. Empirical data comprising qualitative interviews with 28 individuals, sleep diaries, and actigraphy reports (which measure movement as a proxy for sleep) are examined in combination to generate insights into the challenges associated with sleep in recovery from substance misuse. We examine how sleep in recovery involves an alignment of the spatiotemporal rhythms of rehabilitation and the multiple embodied rhythms of individuals. Institutionalised routines reproduce and impose ideas of day/night sleep cycles which are presumed to accord with 'natural' circadian rhythms. Although study participants very much want to achieve these 'natural hegemonies' of sleep, alignment of individual and institutional rhythms is difficult to achieve. We develop the notion of 'sleep waves' as an analytic to capture the multifaceted elements of sleep and to argue that sleep waves recur but are also shaped by complex networks of rhythms, rituals and routines. Sleep waves can become relatively stabilised in rehabilitation settings, but the anticipation of moving on disturbs rhythms and generates anxieties which can affect recovery.

Suppression of the histamine-induced wheal and flare response by fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily and placebo in healthy Japanese volunteers.

BACKGROUND: The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects. OBJECTIVE: To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers. METHODS: Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis. RESULTS: Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to > or = 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels. CONCLUSIONS: Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model.

Development of a portable psychometric testing device for use in the field: an alcohol investigation.

Cognitive and psychomotor performance have traditionally been assessed in the laboratory. There is a need for an objective portable assessment tool to assess cognitive and psychomotor performance. This study investigated the viability of a portable psychometric test battery, in a controlled laboratory environment, possibly leading to use in the field. A randomised, double-blind placebo controlled, three-way crossover design was employed. 16 subjects received 50 mg/100 ml and 80 mg/100 ml of alcohol and alcohol placebo. Performance was assessed with a tracking task, and an attention task presented on a small ruggedised handheld computer. The attention task showed no significant training effects; however, an element of the tracking task did. Statistical significance, effect size, and test-retest reliability analyses are presented indicating sensitivity of the portable psychometric test battery to the impairing effects of two separate doses of alcohol. Ability to undertake wide-scale impairment testing in the field with meaningful results in the absence of baseline data collection may have wide reaching implications, particularly in relation to the assessment of drivers impaired by drug use.

Marital Status, Relationship Distress, and Self-rated Health: What Role for "Sleep Problems"?

This paper analyzes data from a nationally representative survey of adults in the United Kingdom (Understanding Society, N = 37,253) to explore the marital status/health nexus (using categories that include a measure of relationship distress) and to assess the role that sleep problems play as a potential mediator. Findings indicate how it is not just the "form" marital status takes but also the absence or presence of relationship distress that is essential to self-rated health. We demonstrate two further findings that: (1) sleep problems act as a mediator of the link between marital status/relationship distress and self-rated health, most notably for those in cohabiting relationships with medium/high distress or who have a history of relationship loss, and (2) the mediating role of sleep problems differs for divorced men and women.

NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability.

The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this liability, NMR-based screening was implemented to identify alternative zinc-chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to the protein (K(D) = 50 microM) and was identified as a candidate for incorporation into the lead series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved bioavailability. These studies demonstrate that the NMR-based screening of fragments can be effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.

Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization.

Potent inhibitors of 7,8-dihydroneopterin aldolase (DHNA; EC 4.1.2.25) have been discovered using CrystaLEAD X-ray crystallographic high-throughput screening followed by structure-directed optimization. Screening of a 10 000 compound random library provided several low affinity leads and their corresponding X-ray crystal structures bound to the enzyme. The presence of a common structural feature in each of the leads suggested a strategy for the construction of a directed library of approximately 1000 compounds that were screened for inhibitory activity in a traditional enzyme assay. Several lead compounds with IC(50) values of about 1 microM against DHNA were identified, and crystal structures of their enzyme-bound complexes were obtained by cocrystallization. Structure-directed optimization of one of the leads thus identified afforded potent inhibitors with submicromolar IC(50) values.

Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.

A single-center, randomized, double-blind, placebo-controlled, crossover investigation of the effects of fexofenadine hydrochloride 180 mg alone and with alcohol, with hydroxyzine hydrochloride 50 mg as a positive internal control, on aspects of cognitive and psychomotor function related to driving a car.

BACKGROUND: Antihistamines (H(1)-receptor antagonists) are the mainstay of symptomatic therapy for allergic disorders. Antihistamines are needed that cause no disruptive effects on cognitive and psychomotor function. It is essential that antihistamines maintain the integrity of the cognitive system, not only in ambulatory patients at increased risk of drug-induced traffic- or work-related accidents, but also in students and others whose cognitive or intellectual impairment may adversely affect their performance.Objective; The goal of this study was to investigate the acute effects of fexofenadine hydrochloride 180 mg, alone and with a "social" dose of alcohol, on subjective feelings of sedation and on a battery of objective measures related to driving a car. These measures included information processing, psychomotor speed, and reaction time in an on-the-road car-driving task. Hydroxyzine hydrochloride 50 mg was included in the study as a positive internal control to validate the sensitivity of the psychometri tests to nonspecific impairment. METHODS: In this randomized, double-blind, 6-way, crossover study conducted at the Human Psychopharmacology Research Unit, Medical Research Centre (University of Surrey, Guildford, United Kingdom), 18 healthy volunteers received fexofenadine 180 mg, hydroxyzine 50 mg, and placebo alone and with alcohol (0.3 g/kg body weight or approximately 0.43-0.50 g/L blood-alcohol concentration). Treatment periods were separated by a washout period of at least 6 days. Subjects performed tests of cognitive and psychomotor performance at 1, 3, and 5 and hours after dosing. The test battery included subjective ratings of sedation, critical flicker fusion (CFF), choice reaction time (including recognition reaction time [RRT], motor reaction time [MRT], total reaction time [TRT], and brake reaction time [BRT]. RESULTS: Eighteen healthy male volunteers (median age, 30.5 years [range, 23-44 years]) were entered into the study. Fexofenadine alone and with alcohol had no significant effect on performance compared with placebo and was not distinguishable from placebo in any of the objective or subjective tests at any point. However, impairment was evident following the administration of hydroxyzine. Hydroxyzine caused significant impairment in CFF (P < 0.05), RRT (P < 0.001), and TRT (P < 0.001) compared with placebo. Hydroxyzine with alcohol significantly disrupted performance on all of the above measures with respect to both placebo and fexofenadine (P < 0.05) as well as MRT (P < 0.001). No significant treatment effects on BRT were found. CONCLUSION: Fexofenadine 180 mg did not have disruptive effects on objective measures related to driving a car and aspects of psychomotor and cognitive function, even when combined with a dose of alcohol equivalent to 0.3 g/kg body weight, in a study in which the psychometric assessments were shown to be sensitive to impairment.